This proposal describes experiments designed to identify the binding sites and modes of action of anthelmintics such as hycanthones, chlorindazoles, and other compounds in Schistosoma mansoni. This information will lead to the rational development of better and safer anthelmintics. Based on previous studies, and the molecular configuration of many known anthelmintics, it is expected that some of the binding sites will be nucleic acids. No information is yet available on the localization or the true mode of action of these compounds in helminths. Thus six specific goals have been established: 1) The nuclear DNA from S. mansoni will be isolated and purified; any buoyant density satellites observed will be purified; 2) The mitochondrial DNA from S. mansoni will be isolated and purified from mitochondrial fractions; 3) A cell-free, protein-synthesizing system will be developed; 4) various anthelmintics will be studied for their ability to bind to DNA, RNA and protein fractions; inhibitory effects will be determined to elucidate mode of action; 5) The presence or absence of DNA repair replication will be established in normal, drug-treated, and drug-resistant strains of S. mansoni; 6) a new method of visualization of drug-binding sites using high resolution electronmicroscopy is being developed. These studies will provide the first systems for directly determining in schistosomes the mode of action of anthelmintics that interfere with replication, transcription, and translation. The studies on repair replication of DNA may provide the first explanation of the mechanism of hycanthone resistance induced in schistosomes. The new method of visualization of drug-binding by electron microscopy provides an advance of general significance to the study of localization of drugs at the subcellular level.